Cystatin C and Risk of Diabetes and the Metabolic Syndrome - Biomarker and Genotype Association Analyses.

BACKGROUND: We recently reported a relationship between plasma levels of cystatin C and incidence of the metabolic syndrome (MetS) among the first 2,369 subjects who participated in the re-examination study of the population-based Malmö and Diet Cancer Cardiovascular cohort (MDC-CC-re-exam). In this study we aimed to replicate these results and also investigate if cystatin C was causally associated with MetS and diabetes. METHODS: We estimated the effect size of the strongest GWAS derived cystatin C SNP (major allele of rs13038305) on plasma cystatin C in the now completed MDC-CC-re-exam (n = 3,734) and thereafter examined the association between plasma cystatin C (403 cases of diabetes and 2665 controls) as well as rs13038305 (235 cases and 2425 controls) with incident diabetes. The association of rs13038305 and incident MetS (511 cases of MetS and 1980 controls) was similarly investigated in the whole MDC-CC-re-exam. We also attempted to replicate our previously shown association of cystatin C with incident MetS in subjects from the MDC-CC-re-exam (147 cases and 711 controls) that were not included in our previous report. RESULTS: In the entire MDC-CC-re-exam, each copy of the major allele of rs13038305 was associated with approximately 0.30 standard deviation (SD) higher plasma concentration of cystatin C (ß = 0.33, p = 4.2E-28) in age and sex adjusted analysis. Cystatin C in plasma was not associated with incident diabetes after adjustment for known diabetes risk factors (OR per 1 SD increment 0.99 (0.86-1.13), p = 0.842). In the replication cohort of MDC-CC-re-exam, the OR (95% CI) for incident MetS in subjects belonging to quartiles 1, 2, 3 and 4 of plasma cystatin C levels was 1.00 (reference), 1.21 (0.70-2.07), 1.62 (0.95-2.78) and 1.72 (1.01-2.93) (ptrend = 0.026) in age and sex adjusted analysis. In the entire MDC-CC-re-exam the odds ratio for incident MetS and diabetes per copy of the major rs13038305 allele was 1.13, (0.95-1.34), p = 0.160 and 1.07, 95% CI 0.89-1.30, p = 0.478, respectively. CONCLUSION: We were able to replicate our previously shown association between high levels of cystatin C and increased risk of future development of MetS. However, a causal involvement of cystatin C in the etiology of MetS or diabetes seems unlikely since genetic elevation of plasma cystatin C was not significantly related to incidence of these diseases.

Cystatin C Is Not Causally Related to Coronary Artery Disease.

BACKGROUND: Strong and independent associations between plasma concentration of cystatin C and risk of cardiovascular disease (CVD) suggests causal involvement of cystatin C. AIM: The aim of our study was to assess whether there is a causal relationship between plasma concentration of cystatin C and risk of coronary artery disease (CAD) using a Mendelian Randomization approach. METHODS: We estimated the strength of association of plasma cystatin C on CAD risk and the strength of association of the strongest GWAS derived cystatin C SNP (rs13038305) on plasma cystatin C in the population-based Malmö Diet and Cancer Study (MDC) and thereafter the association between rs13038305 and CAD in the MDC (3200 cases of CAD and 24418 controls) and CARDIOGRAM (22233 cases of CAD and 64762 controls). RESULTS: Each standard deviation (SD) increment of plasma cystatin C was associated with increased risk of CAD (OR = 1.20, 95% CI 1.07-1.34) after full adjustment. Each copy of the major allele of rs13038305 was associated with 0.34 SD higher plasma concentration of cystatin C (P<1 x 10-35), resulting in a power of >98% to detect a significant relationship between rs13038305 and CAD in MDC and CARDIOGRAM pooled. The odds ratio for CAD (per copy of the major rs13038305 allele) was 1.00 (0.94-1.07); P = 0.92 in MDC, 0.99 (0.96-1.03); P = 0.84 in CARDIOGRAM and 1.00 (0.97-1.03); P = 0.83 in MDC and CARDIOGRAM pooled. CONCLUSION: Genetic elevation of plasma cystatin C is not related to altered risk of CAD, suggesting that there is no causal relationship between plasma cystatin C and CAD. Rather, the association between cystatin C and CAD appears to be due to the association of eGFR and CAD.

A functional variant of the NEDD4L gene is associated with beneficial treatment response with ß-blockers and diuretics in hypertensive patients.

OBJECTIVE: The capability of the protein NEDD4L to reduce renal tubular expression of epithelial Na+ channel (ENaC) is influenced by a functional rs4149601 G→A NEDD4L polymorphism. As diuretics and ß-blockers inhibit renal sodium reabsorption and renin release, respectively, we hypothesized that the ß-blocker or diuretic-induced blood pressure reduction and prevention of cardiovascular disease would be greater in patients with the highest ENaC expression (rs4149601 G-allele), whereas there would be no such genetically mediated differences in treatment efficacy among patients treated with the vasodilator diltiazem. METHODS: We related rs4149601 status to 6-month blood pressure reduction and risk of cardiovascular events in 5152 hypertensive patients (DBP ≥ 100 mmHg) from the Nordic Diltiazem Study (NORDIL) randomized to either ß-blocker and/or diuretic-based treatment or diltiazem-based treatment. RESULTS: In patients on ß-blocker or diuretic monotherapy, carriers of the G-allele had greater SBP reduction (19.5 ± 16.8 vs. 15.0 ± 19.3 mmHg, P < 0.001) and DBP reduction (15.4 ± 8.3vs. 14.1 ± 8.4 mmHg, P = 0.02) and during 4.5 years of follow-up among patients randomized to ß-blockers and/or diuretics, carriers of the G-allele had greater protection from cardiovascular events [relative risk (RR) = 0.52, 95% confidence interval (CI) = 0.36-0.74, P < 0.001] as compared to AA homozygotes. Within the diltiazem group, there was no difference in blood pressure reduction or risk of cardiovascular events according to genotype. CONCLUSION: The functional NEDD4L rs4149601 polymorphism influences the efficacy of ß-blocker and/or diuretic-based antihypertensive treatment both in terms of blood pressure reduction and cardiovascular disease protection, whereas diltiazem-based antihypertensive treatment efficacy is not influenced by this NEDD4L polymorphism.

Interaction between renal function and microalbuminuria for cardiovascular risk in hypertension: the nordic diltiazem study.

We investigated whether renal function and microalbuminuria are independent predictors and whether any interaction exists between them, regarding future cardiovascular disease in hypertensive patients (n=10 881) followed for 4.5 years. The primary end points (PEs) were fatal and nonfatal myocardial infarction and stroke and other cardiovascular deaths. Creatinine and glomerular filtration rate (GFR), estimated using the formulas of the Modification of Diet in Renal Disease study group and Cockroft and Gault and in a subsample (n=4929) of microalbuminuria and interaction terms of microalbuminuria and renal function, were related to the risk of the PE using Cox proportional hazards model after full adjustment. Increased creatinine (P<0.001), decreased GFR from Cockroft and Gault (P=0.001), and decreased GFR from the Modification of Diet in Renal Disease study group (P=0.001) were all independent risk factors for the PE. Stepwise exclusion of patients with the poorest renal function excluded the possibility that the relationship between decreasing renal function and the PE was driven only by patients with severely impaired renal function. Microalbuminuria and all 3 of the indices of renal function predicted the PE independent of each other. There was a significant interaction between microalbuminuria and GFR from Cockroft and Gault (P=0.040) in prediction of the PE. Both renal function and microalbuminuria add independent prognostic information regarding cardiovascular risk in hypertensive patients. The cardiovascular risk associated with microalbuminuria increases with a decline in GFR, as demonstrated by a significant interaction between microalbuminuria and GFR from Cockroft and Gault. Because estimation of the total cardiovascular risk is essential for the aggressiveness of risk factor interventions, simultaneous inclusion of GFR and microalbuminuria in global cardiovascular risk assessment is essential.

Comparison between ventricular gradient and a new descriptor of the wavefront direction of ventricular activation and recovery.

BACKGROUND: Total R T cosine (TCRT) is a new descriptor of repolarization heterogeneity that quantifies the deviation between the directions of ventricular depolarization and repolarization. It revives the old concept of ventricular gradient (VG). HYPOTHESIS: Our goal was to examine whether TCRT and VG contain nonredundant information by comparing their reaction to autonomic tests, namely, postural changes and Valsalva maneuver. METHODS: Digital 12-lead electrocardiograms were recorded in 16 patients with cardiovascular syndrome X (SX, chest pain, exercise-induced ST-depression, normal coronary arteries, 3 men, age 60 +/- 9 years) and 40 healthy volunteers (31 men, age 33 +/- 7 years) during postural changes and Valsalva maneuver. The angle (VGA) [degrees] and magnitude (VGM) [ms.mV] of VG in reconstructed XYZ leads and TCRT (average cosine of the angles between the QRS and T vectors in mathematically reconstructed three-dimensional space) were calculated. RESULTS: (mean +/- standard of the mean): In healthy subjects, VGM and TCRT decreased, whereas VGA increased in the sitting and standing compared with supine position (TCRT: 0.61 +/- 0.05,0.47 +/- 0.06,0.29 +/- 0.08, supine, sitting, and standing, p < 0.05) and during phase II Valsalva (TCRT: 0.47 +/- 0.06 vs. 0.61 +/- 0.05, p < 0.01 in supine, 0.24 +/- 0.08 vs. 0.37 +/- 0.07, p < 0.01 in standing). In patients with SX, VGM decreased in the standing position, VGA did not change significantly, while TCRT decreased only in patients without T-wave abnormalities (n = 9) (TCRT in standing and supine: 0.55 +/- 0.09 vs. 0.68 +/- 0.08, p < 0.05). VG(M) increased during Valsalva in patients with SX. Total R T cosine correlated strongly with VGA (r = -0.84, p < 0.00001) and, unlike VGM, did not correlate with heart rate. CONCLUSIONS: Ventricular gradient and TCRT contain nonredundant information. In healthy subjects, they react sensitively to autonomic provocation. In patients with SX, their reaction is attenuated, which suggests disturbance of the autonomic control of repolarization.